Cholinergic receptors in aging and early Alzheimer?s disease: longitudinal change David Sultzer, MD VA Greater Los Angeles Healthcare System Abstract The overall goal of this study is to evaluate the role of the brain cholinergic neurotransmitter system in cognitive aging and the progression to Alzheimer?s disease (AD). The study examines changes in nicotinic cholinergic receptor binding over time among healthy older Veterans and those with mild cognitive impairment (MCI) and measures the association between receptor binding change and clinical cognitive change. Memory decline with aging and AD are now critical healthcare challenges as the Veteran population ages. While several neurobiological factors contribute to cognitive aging and the neurodegenerative cascade of AD, their individual and interactive roles are poorly understood, the involvement of neurotransmitter systems has not been well-studied, and efficacious targeted treatments have been elusive. The cholinergic neurotransmitter system has been shown to play a key role in the cognitive changes associated with aging and AD. Recently, our group has used a novel PET imaging ligand, 2-18F-fluoro-3- (2(S)azetidylmethoxy) pyridine (2FA) to measure nicotinic cholinergic receptor binding in vivo in healthy older adults and those with MCI and AD. Results indicate that binding is modestly reduced regionally in MCI and more extensively reduced in mild and moderate AD. In the healthy and MCI groups, 2FA binding is inversely associated with age and cognitive deficits. Reduced binding is not solely a reflection of hippocampal atrophy in a preliminary analysis. The emerging model postulates that nicotinic receptor binding dysfunction is a primary event in aging and early AD neurodegeneration. This receptor dysfunction alters downstream neurotransmitter release, synaptic plasticity in key structures, and function across neural systems, with distinct clinical consequences. The proposed project takes the next step to evaluate longitudinal change in the nicotinic cholinergic system: Healthy older Veterans and those with MCI undergo 2FA PET imaging and cognitive assessment, with repeat assessments at least two years later. Change in regional nicotinic cholinergic receptor binding will be measured and relationships between binding changes and changes in memory, attention, and global cognition will be assessed. The relative contribution of atrophy in two structures related to acetylcholine availability and post-receptor translational effects, the basal forebrain and hippocampus, are also explored. In addition, participants undergo FDG-PET imaging to measure metabolic activity in cortical regions known to be affected by AD. Thus, the decline in nicotinic cholinergic receptor binding, associations with cognitive changes, and the influence of basal forebrain and hippocampal atrophy can be assessed in the context of a likely AD neurodegenerative process. Results from this study can better define the role of regional cholinergic receptor binding in the expression of aging-related cognitive changes and the progression towards AD, and considers the interactive contribution of atrophy in key brain structures. Overall, the project contributes to a specific cholinergic model of cognitive aging and early AD and can offer an in vivo tool to aid treatment development.